1. Field of Invention
This invention relates to a solid synthetic pulmonary surfactant and a method of manufacturing thereof.
2. Description of Related Art
Pulmonary surfactant (also referred to as “lung surfactant”) is a complex mixture of lipids and proteins that promotes the formation of a monolayer at the alveolar air-water interface, and by reducing the surface tension, prevents the collapse of the alveolus during expiration. Lung surfactant lines the alveolar epithelium of mature mammalian lungs. Natural lung surfactant has been described as a “lipoprotein complex” because it contains both phospholipids and apoproteins that interact to reduce surface tension at the lung air-liquid interface. Four proteins have been found to be associated with lung surfactant, namely SP-A, SP-B, SP-C, and SP-D. Specifically, SP-B appears to be essential for the biophysical action of lung surfactant. It is accepted therapy for the treatment of a variety of respiratory disorders to administer lung surfactant to the patient's lungs.
From a pharmacological point of view, the optimal exogenous lung surfactant to use in the treatment would be completely synthesized in the laboratory. In this regard, one mimetic of SP-B that has found to be useful is KL4, which is a 21 amino acid cationic polypeptide.
One method of manufacturing lung surfactant on a commercial-scale for medical use is by a process that utilizes a thin film evaporator (TFE) unit operation. The process as it applies to the production of KL4 lung surfactant consists of the following steps: 1) solubilizing the four primary formulation components, dipalmitoyl phosphatidylcholine (DPPC), palmitoyloleoyl phosphatidylglycerol (POPG) and palmitic acid (PA) and KL4 in ethanol; 2) removing the ethanol utilizing the TFE; and 3) dispensing the final dispersion into vials. The TFE unit operation itself is complex and has scaling limitations. Specifically, a 1 ft2 TFE produces a 40-liter batch and the biggest comparable unit available is a 10 ft2 TFE. This restricts the batch size, which is undesirable as additional indications are approved for the KL4 surfactant requiring ever increasing amounts of surfactant. Moreover, the process is performed under aseptic conditions that contribute significantly to the cost, scheduling flexibility, and complexity of the product.
In addition to the cost and complexity of using a TFE, a further complication exists due to the composition being stored in a liquid state. Because the polypeptide and lipid components of the composition are subject to degradation, the solution must be kept refrigerated to retard any degradation and achieve long term stability.
Lyophilization or freeze-drying is an important process in manufacturing solid pharmaceutical formulations. Solid formulations have longer stability than liquid formulations and are easier to transport and store. During the lyophilization process, a pharmaceutical formulation can be dried to 2% or less of residual moisture content without raising a temperature above 30° C. Therefore, this process is less likely to cause thermal degradation of formulations than a high temperature process such as, for example, spray drying.
The lyophilization process involves freezing a liquid formulation and removing the solvent associated with it by direct sublimation from the solid phase to the vapor phase without passing through the intermediate liquid phase. Generally, the lyophilization process consists of three stages, freezing stage, primary drying, and secondary drying.
Freezing is the process of solidification of a starting liquid by means of cooling the material below a given temperature less than or equal to 0° C. Primary drying is the portion of the lyophilization cycle in which sublimation of a majority of the frozen solvents are removed while the material is kept below a threshold temperature in order to maintain the structure established during the freeze. Secondary drying is the process of desorption of a portion of the residual moisture and is usually conducted at temperatures of 25° C. and above. The critical process parameters associated with each of these three steps are shelf temperature, chamber pressure and time.
Lyophilization process continues to evolve through decades. Despite ample knowledge developed in this area, the challenges of producing a uniformly distributed cake having mechanically stable structure on a commercial scale at a reasonable cost and time remain.
U.S. Pat. No. 5,952,303 to Bornstein describes a lyophilized synthetic pulmonary surfactant obtained by lyophilizing aqueous suspension of a combination of phospholipids, palmitic acid and a peptide.
U.S. Pat. No. 7,582,312 to Johnson describes a process of making a lyophilized synthetic pulmonary surfactant by lyophilizing a liquid formulation of phospholipids, palmitic acid and a peptide in a solvent system containing 20% or more of organic solvent.
Using the lyophilization processes described in the patents above for lyophilization of a liquid synthetic pulmonary surfactant having organic solvent in a range from 5% and above to less than 20% yielded fragile and collapsed material unacceptable for commercial distribution. Manufacturing of a synthetic pulmonary surfactant using previously described lyophilization cycles resulted in material lifting from the bottom of the vial (“levitation”) which would result in reduced heat transfer, non-uniform heat distribution and yield product of varying quality attributes such as physical morphology and residual moisture.
Therefore, there is a need for improved methods of producing lung surfactant compositions and improved lung surfactant compositions. The present invention presents a solution to the problem of manufacturing a dry synthetic pulmonary surfactant, which is chemically and mechanically stable, without compromising its biological activity in the lyophilization process.
All references cited herein are incorporated herein by reference in their entireties.